This invention relates to novel endothelin receptor antagonists, derivatives, and pharmaceutically acceptable acid addition salts thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by compounds that block the endothelin signaling pathway that leads to vasoconstriction and in particular those diseases or conditions beneficially treated by endothelin receptor antagonists.
Bosentan is known by the chemical names N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tert-butyl-benzenesulfonamide and 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]-bipyrimidin-4-yl]-benzenesulfonamide.
Bosentan is a tetrasubstituted pyrimidine derivative that was reported in U.S. Pat. No. 5,292,740 to be useful for treating circulatory disorders, such as hypertension. Bosentan is now known to be a dual endothelin receptor antagonist that blocks the binding of endothelin to both the ETA and ETB receptors.
Endothelin-1 (ET-1), a 21-amino acid peptide neurohormone, was first isolated and described in 1998 and is an extremely potent and long-acting vasoconstrictor (Itoh, Y et al, FEBS Lett 1988, 231:440). ET-1 causes vasoconstriction by binding to ETA and ETB, which are receptors in the endothelium and vascular smooth muscle. ET-1 levels are elevated in the plasma and lung tissue of patients with pulmonary arterial hypertension, which suggests that ET-1 has a pathogenic role in this disease. Bosentan is believed to work by competitively and specifically binding to ETA and ETB receptor sites in the endothelium and vascular smooth muscle with a slightly higher affinity for ETA than for ETB. This binding inhibits ET-1 from binding to ETA and/or ETB, which interferes with a signaling pathway that is responsible for causing vasoconstriction.
Bosentan has been approved by the Food and Drug Administration to treat the symptoms of pulmonary arterial hypertension, high blood pressure within the main artery that carries blood from the heart's right ventricle to the lungs. Bosentan has been shown to be effective in decreasing the constriction this artery, thereby increasing the supply of blood to the lungs and reducing the workload incurred by the heart.
Bosentan has been reported to have a half-life in humans of approximately five hours and is eliminated mainly through hepatic metabolism, followed by biliary excretion of three metabolites (see Center for Drug Evaluation and Research Approval Package for Application Number 21-290; Clinical Pharmacology and Biopharmaceutics Review; Aug. 16, 2001). One of these metabolites, hydroxybosentan, is active and responsible for up to 20% of the overall pharmaceutical properties of bosentan.
Bosentan is typically administered twice per day due to its short half-life. Multiple dosing can lead to compliance problems such as missed doses and overdosing when compensating for missed doses. Moreover, bosentan may cause liver damage due to bilary excretion and birth defects if taken during pregnancy. Thus, bosentan cannot be safely administered to patients who are pregnant or who suffer from liver impairment. Less serious side-effects of bosentan include headache, nasopharyngitis, flushing, edema of the lower limbs, hypotension, and palpitations. Bosentan may also decrease the effectiveness of hormonal contraceptives, regardless of the route of administration. Bosentan may also irreversibly lower sperm count in some men. These side effects may be attributable to one or more of the metabolites of bosentan and/or overdosing due to poor compliance.
Despite the beneficial activities of bosentan, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.